1. Field of the Invention
The invention relates generally to the monitoring of analytes in the body and the transdermal delivery of drugs to the body. More particularly, the invention relates to enhancing the rate of flux of a substance collected from or delivered to a biological tissue through the poration of the skin or other biological membrane and the application of a flux enhancer to the porated biological membrane.
2. Description of Related Art
The transfer of materials across biological membranes is necessary in the practice of a variety of medical and other procedures. For example, to minimize complications resulting from diabetes, diabetics must periodically monitor and control their blood glucose levels. Typically, blood glucose monitoring is achieved by taking a sample of blood or other body fluid, and measuring the glucose level present in the sample. Historically, the samples have been obtained by piercing the skin with a needle or lancet. It is also frequently necessary to deliver a drug through the skin or other biological membrane. Most frequently, drugs are delivered transdermally by injection with a needled syringe. Such invasive sampling and drug delivery methods entail a number of disadvantages, most notably, discomfort and potential infection.
In an effort to address the inherent disadvantages of invasive sampling and delivery methods, several minimally invasive and non-invasive sampling and delivery techniques have been developed. xe2x80x9cMinimally invasive,xe2x80x9d as used herein, refers to techniques in which a biological membrane or tissue is invaded by forming small holes or micropores in the surface of a tissue or membrane, but do not substantially damage the underlying, non-surface portions of the tissue or membrane. As used herein, xe2x80x9cnon-invasivexe2x80x9d refers to techniques not requiring the entry of a needle, catheter, or other invasive medical instrument into the body. It has previously been discovered that blood glucose levels can be determined from an analysis of interstitial fluid, the clear fluid occupying the spaces between cells in the body, samples of which can be obtained through the skin by previously known minimally invasive or non-invasive sampling techniques. Previously known minimally invasive or noninvasive methods of sampling interstitial fluid, however, have not been fully successful for blood glucose monitoring purposes. One challenge facing minimally invasive or non-invasive methods is the ability to acquire a large enough sample of interstitial fluid in a short time to enable accurate glucose measurement with low cost disposable assay techniques.
The skin presents the largest, most readily accessible biological membrane through which an analyte may be collected or a drug delivered. Mucosal and buccal membranes present feasible, but less accessible, sites for collection and delivery. Unfortunately, the skin and, to a somewhat lesser extent, the mucosal and buccal membranes, are highly resistant to the transfer of materials therethrough. The skin generally comprises two main parts: the epidermis and the dermis. The epidermis forms the outer portion of the skin, and itself comprises several distinct layers. The outermost layer of the epidermis, the stratum corneum, is composed of denucleated, keratinized, clear, dead cells, and is typically between 10-30 xcexcm thick. The stratum corneum is chiefly responsible for the skin""s barrier properties and, therefore, is the layer of skin forming the primary obstacle to the transdermal flux of analytes out of the body and of drugs or other foreign materials or organisms into the body.
There have been significant advancements made in the transdermal transport of substances across a biological membrane by creating micropores in the biological membrane. See, for example, U.S. Pat. No. 5,885,211, entitled xe2x80x9cMicroporation of Human Skin for Drug Delivery and Monitoring Applicationsxe2x80x9d, the entirety of which is incorporated herein by reference. Nevertheless, there is a need to improve upon these techniques and particularly increase the rate at which substances are transported through a biological membrane.
Briefly, one aspect of the present invention involves a method for enhancing the flux rate of a fluid through biological tissue. The method generally comprises the delivering an effective amount of a flux enhancer into the tissue through at least one micropore in the tissue. Depending on the specific application, the flux enhancer is delivered to the micropore through any of a number of mechanisms, examples of which are described below. The depth of poration and of application of the flux enhancer can also be adjusted to suit the desired application.
Another aspect of the present invention involves a method of harvesting an analyte from tissue beneath a biological membrane. The method preferably includes the steps of porating the biological membrane to form at least one micropore, delivering an effective amount of a flux enhancer to the tissue through the micropore, and collecting a quantity of the analyte through the micropore. Again, the mechanism for delivering the flux enhancer can vary to suit the application, as can the depth of poration and application of the flux enhancer. The application of a motive force, such as suction, pressure, electric field, sonic energy, or concentration gradient, can also be employed to further enhance the rate of analyte harvesting.
Yet another embodiment of the present invention provides a method of delivering a drug through a biological membrane. The method preferably comprises porating a site of the membrane to form at least one micropore, delivering an effective amount of a flux enhancer into the micropore, and introducing a drug through the at least one micropore. Again, the mechanism for delivering the flux enhancer can vary to suit the application, as can the depth of poration and application of the flux enhancer. The application of a motive force, such as iontophoresis, pressure, electric field, sonic energy, or concentration gradient can also be employed to further enhance the rate of drug delivery into the tissue.
Still a further aspect of the present invention provides involves a device for facilitating the formation of micropores in a biological membrane and for enhancing the rate of flux of a fluid therethrough.